The contact sensitization of 11 simple coumarins was examined by subcutaneous sensitizing of guinea pigs, and the structure-activity relationship and cross-reactivity were investigated. Esculetin, 4-methylesculetin, and daphnetin were found to be strong sensitizers, and 4-hydroxy-coumarin to be a moderate sensitizer. Other simple coumarins tested hed a weak sensitivity to mild sensitizers. The results suggest that the introduction of hydroxy group, especially adjacent substitution at the 6, 7,

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... nd 8 positions of the coumarin ring with two hydroxy groups, may play an important role in exhibiting the contact sensitization activity. The cross-reactivity was observed between esculetin and 4-methylesculetin, esculin or isoscoporetin, and also between daphnetin and 4-methylumbelliferone or umbelliferone, although there was no mutual cross-reactivity between esculetin and daphnetin. It is interesting to note that guinea pigs, which had a weak sensitivity to umbelliferone, showed a strong cross-reactivity to daphnetin, while those, which had a weak sensitivity to daphnetin, showed a weak cross-reactivity to umbelliferone. It is assumed that a skin-protein conjugation at 5 or 6 positions of the coumarin ring is important to elicit the cross-reactivity of esculetin or daphnetin groups.